Fumigillol compounds and methods of making and using same

ABSTRACT

The disclosure provides fumagillol type compounds and their use in treating medical disorders, such as obesity. Pharmaceutical compositions and methods of using, e.g. in the treatment of obesity are provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/399,392, filed Nov. 6, 2014, which is a national stage filing under35 U.S.C. §371 of PCT/US2013/040080, filed May 8, 2013, which claimspriority to U.S. Provisional Ser. No. 61/644,612, filed May 9, 2012, allof which are hereby incorporated by reference in their entirety.

BACKGROUND

Over 1.1 billion people worldwide are reported to be overweight. Obesityis estimated to affect over 90 million people in the United Statesalone. Twenty-five percent of the population in the United States overthe age of twenty is considered clinically obese. While being overweightor obese presents problems (for example restriction of mobility,discomfort in tight spaces such as theater or airplane seats, socialdifficulties, etc.), these conditions, in particular clinical obesity,affect other aspects of health, i.e., diseases and other adverse healthconditions associated with, exacerbated by, or precipitated by beingoverweight or obese. The estimated mortality from obesity-relatedconditions in the United States is over 300,000 annually (O'Brien et al.Amer J Surgery (2002) 184:4S-8S; and Hill et al. (1998) Science,280:1371).

There is no curative treatment for being overweight or obese.Traditional pharmacotherapies for treating an overweight or obesesubject, such as serotonin and noradrenergic re-uptake inhibitor,noradrenergic re-uptake inhibitors, selective serotonin re-uptakeinhibitors, intestinal lipase inhibitors, or surgeries such as stomachstapling or gastric banding, have been shown to provide minimalshort-term benefits or significant rates of relapse, and have furthershown harmful side-effects to patients.

MetAP2 encodes a protein that functions at least in part byenzymatically removing the amino terminal methionine residue fromcertain newly translated proteins such as glyceraldehyde-3-phosphatedehydrogenase (Warder et al. (2008) J Proteome Res 7:4807). Increasedexpression of the MetAP2 gene has been historically associated withvarious forms of cancer. Molecules inhibiting the enzymatic activity ofMetAP2 have been identified and have been explored for their utility inthe treatment of various tumor types (Wang et al. (2003) Cancer Res63:7861) and infectious diseases such as microsporidiosis,leishmaniasis, and malaria (Zhang et al. (2002) J Biomed Sci. 9:34).Notably, inhibition of MetAP2 activity in obese and obese-diabeticanimals leads to a reduction in body weight in part by increasing theoxidation of fat and in part by reducing the consumption of food(Rupnick et al. (2002) Proc Natl Acad Sci USA 99:10730).

Such MetAP2 inhibitors may be useful as well for patients with excessadiposity and conditions related to adiposity including type 2 diabetes,hepatic steatosis, and cardiovascular disease (via e.g. by amelioratinginsulin resistance, reducing hepatic lipid content, and reducing cardiacworkload). Accordingly, compounds capable of modulating MetAP2 areneeded to address the treatment of obesity and related diseases as wellas other ailments favorably responsive to MetAP2 modulator treatment.

SUMMARY

The disclosure provides, for example, compounds which may be modulatorsof MetAP2, and their use as medicinal agents, processes for theirpreparation, pharmaceutical compositions containing them as an activeingredient both alone or in combination with other agents, to their useas medicaments and to their use in the manufacture of medicaments forthe use in the inhibition of MetAP2 activity in warm-blooded animalssuch as humans. In particular this invention relates to compounds usefulfor the treatment of obesity, type 2 diabetes, and otherobesity-associated conditions. Also provided are pharmaceuticalcompositions comprising at least one disclosed compound and apharmaceutically acceptable carrier.

In an embodiment, provided herein are compounds represented by, forexample,

and pharmaceutically acceptable salts, and/or stereoisomers, thereof,wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are described herein.

Also provided herein are compounds:

Also provided herein are methods of treating obesity in a patient inneed thereof, comprising administering an effective amount of adisclosed compound.

DESCRIPTION OF FIGURES

FIG. 1 compares the body weight loss in a mouse model using 0.3 mg/kgsubcutaneous dosing of disclosed compounds.

FIGS. 2A, 2B, and 2C compares the body weight loss in a mouse modelusing e.g., 3 mg/kg oral dosing of disclosed compounds.

FIGS. 3A, 3B, 3C depict the concentration of a testes biomarker afteradministration of compounds in the mouse model of FIG. 2 and indicatesthe availability or non-availability of the tested compounds to thetestes tissue. FIG. 3C indicate that e.g, compound 444 is not availabileto the testes tissue.

DETAILED DESCRIPTION

The features and other details of the disclosure will now be moreparticularly described. Before further description of the presentinvention, certain terms employed in the specification, examples andappended claims are collected here. These definitions should be read inlight of the remainder of the disclosure and understood as by a personof skill in the art. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood by a person of ordinary skill in the art.

Definitions

“Treating” includes any effect, e.g., lessening, reducing, modulating,or eliminating, that results in the improvement of the condition,disease, disorder and the like.

“Pharmaceutically or pharmacologically acceptable” include molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to an animal, or a human, asappropriate. For human administration, preparations should meetsterility, pyrogenicity, general safety and purity standards as requiredby FDA Office of Biologics standards.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” as used herein refers to any and all solvents,dispersion media, coatings, isotonic and absorption delaying agents, andthe like, that are compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances iswell known in the art. The compositions may also contain other activecompounds providing supplemental, additional, or enhanced therapeuticfunctions.

The term “pharmaceutical composition” as used herein refers to acomposition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

“Individual,” “patient,” or “subject” are used interchangeably andinclude any animal, including mammals, preferably mice, rats, otherrodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates,and most preferably humans. The compounds of the invention can beadministered to a mammal, such as a human, but can also be administeredto other mammals such as an animal in need of veterinary treatment,e.g., domestic animals (e.g., dogs, cats, and the like), farm animals(e.g., cows, sheep, pigs, horses, and the like) and laboratory animals(e.g., rats, mice, guinea pigs, and the like). The mammal treated in themethods of the invention is desirably a mammal in which treatment ofobesity, or weight loss is desired. “Modulation” includes antagonism(e.g., inhibition), agonism, partial antagonism and/or partial agonism.

In the present specification, the term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. The compounds of the invention are administered intherapeutically effective amounts to treat a disease. Alternatively, atherapeutically effective amount of a compound is the quantity requiredto achieve a desired therapeutic and/or prophylactic effect, such as anamount which results in weight loss.

The term “pharmaceutically acceptable salt(s)” as used herein refers tosalts of acidic or basic groups that may be present in compounds used inthe present compositions. Compounds included in the present compositionsthat are basic in nature are capable of forming a wide variety of saltswith various inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to malate, oxalate, chloride, bromide, iodide, nitrate, acetate,tartrate, oleate, fumarate, formate, benzoate, glutamate,methanesulfonate, benzenesulfonate, and p-toluenesulfonate salts.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present invention encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as geometric isomers,enantiomers or diastereomers. The enantiomer and diastereomers may bedesignated by the symbols “(+),” “(−).” “R” or “S,” depending on theconfiguration of substituents around the stereogenic carbon atom, butthe skilled artisan will recognize that a structure may denote a chiralcenter implicitly. Geometric isomers, resulting from the arrangement ofsubstituents around a carbon-carbon double bond or arrangement ofsubstituents around a cycloalkyl or heterocyclic ring, can also exist inthe compounds of the present invention. The symbol ═ denotes a bond thatmay be a single, double or triple bond as described herein. Substituentsaround a carbon-carbon double bond are designated as being in the “Z” or“E” configuration wherein the terms “Z” and “E” are used in accordancewith IUPAC standards. Unless otherwise specified, structures depictingdouble bonds encompass both the “E” and “Z” isomers. Substituents arounda carbon-carbon double bond alternatively can be referred to as “cis” or“trans,” where “cis” represents substituents on the same side of thedouble bond and “trans” represents substituents on opposite sides of thedouble bond. The arrangement of substituents around a carbocyclic ringcan also be designated as “cis” or “trans.” The term “cis” representssubstituents on the same side of the plane of the ring and the term“trans” represents substituents on opposite sides of the plane of thering. Mixtures of compounds wherein the substituents are disposed onboth the same and opposite sides of plane of the ring are designated“cis/trans.”

The term “stereoisomers” when used herein consist of all geometricisomers, enantiomers or diastereomers. The present invention encompassesvarious stereoisomers of these compounds and mixtures thereof.

Individual enantiomers and diasteriomers of compounds of the presentinvention can be prepared synthetically from commercially availablestarting materials that contain asymmetric or stereogenic centers, or bypreparation of racemic mixtures followed by resolution methods wellknown to those of ordinary skill in the art. These methods of resolutionare exemplified by (1) attachment of a mixture of enantiomers to achiral auxiliary, separation of the resulting mixture of diastereomersby recrystallization or chromatography and liberation of the opticallypure product from the auxiliary, (2) salt formation employing anoptically active resolving agent, (3) direct separation of the mixtureof optical enantiomers on chiral liquid chromatographic columns or (4)kinetic resolution using steroselective chemical or enzymatic reagents.Racemic mixtures can also be resolved into their component enantiomersby well known methods, such as chiral-phase gas chromatography orcrystallizing the compound in a chiral solvent. Stereoselectivesyntheses, a chemical or enzymatic reaction in which a single reactantforms an unequal mixture of stereoisomers during the creation of a newstereocenter or during the transformation of a pre-existing one, arewell known in the art. Stereoselective syntheses encompass both enantio-and diastereoselective transformations. For examples, see Carreira andKvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim,2009.

The compounds disclosed herein can exist in solvated as well asunsolvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. In one embodiment, thecompound is amorphous. In one embodiment, the compound is a polymorph.In another embodiment, the compound is in a crystalline form.

The invention also embraces isotopically labeled compounds of theinvention which are identical to those recited herein, except that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as ²H, ³H ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. For example, a compoundof the invention may have one or more H atom replaced with deuterium.

Certain isotopically-labeled disclosed compounds (e.g., those labeledwith ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence form a contemplated alternativeembodiment. Isotopically labeled compounds of the invention cangenerally be prepared by following procedures analogous to thosedisclosed in the e.g., Examples herein by substituting an isotopicallylabeled reagent for a non-isotopically labeled reagent.

In certain embodiments, the present disclosure provides compoundsrepresented by:

wherein R¹ is H or C₁₋₃alkyl; or pharmaceutically acceptable salts orstereoisomers thereof. For example, contemplated herein is a compoundrepresented by:

Also provided herein are compounds represented by:

wherein

R² is selected from the group consisting of H, hydroxyl, and C₁₋₄ alkyl(optionally substituted with hydroxyl and/or halo) e.g., isopropyl(optionally substituted with a hydroxyl and/or halo);

R³ is selected from the group consisting of H, and hydroxyl; orpharmaceutically acceptable salts or stereoisomers thereof. In otherembodiments, R² may be C₁₋₄ alkyl, optionally substituted with ahydroxyl.

Contemplated herein is a compound represented by:

wherein

R⁴ and R⁵ are each methyl; or

R⁴ and R⁵, together with the nitrogen to which they are attached, form a4-5 membered ring optionally substituted by one or two substituentsindependently selected from the group consisting of methyl and hydroxyl;or pharmaceutically acceptable salts or stereoisomers thereof. Forexample, contemplated herein are compounds represented by:

whereinR⁶ is selected from the group consisting of H, hydroxyl or methyl; andR⁷ is selected from the group consisting of H, hydroxyl or methyl.

whereinR′ is methyl;R″ is H or methyl; or pharmaceutically acceptable salts or stereoisomersthereof.

Also contemplated herein is a compound represented by:

wherein n is 0, 1 or 2; or pharmaceutically acceptable salts orstereoisomers thereof.

In a particular embodiment, contemplated compounds include thoseselected from the group represented by:

or pharmaceutically acceptable salts or stereoisomers thereof.

Exemplary compounds include:

and pharmaceutically salts or stereoisomers thereof.

Another aspect of this disclosure provides methods of modulating theactivity of MetAP2. Such methods comprise exposing said receptor to acompound described herein. The ability of compounds described herein tomodulate or inhibit MetAP2 can be evaluated by procedures known in theart and/or described herein. Another aspect of the invention providesmethods of treating a disease associated with expression or activity ofMetAP2 in a patient. For example, a contemplated method includesadministering a disclosed compound in an amount sufficient to establishinhibition of intracellular MetAP2 effective to increase thioredoxinproduction in the patient and to induce multi organ stimulation ofanti-obesity processes in the subject, for example, by administering adisclosed compound in an amount insufficient to reduce angiogenesis inthe patient.

In certain embodiments, the disclosure provides a method of treating andor ameliorating obesity in a patient by administering an effectiveamount of a disclosed compound. Also provided herein are methods forinducing weight loss in a patient in need thereof.

Other contemplated methods of treatement include method of treating oramelioriating an obesity-related condition or co-morbidity, byadministering a compound disclosed herein to a subject. For example,contemplated herein are methods for treating type 2 diabetes in apatient in need thereof.

Exemplary co-morbidities or other disorders that may be treated by adisclosed compound may include cardiac disorders, endocrine disorders,respiratory disorders, hepatic disorders, skeletal disorders,psychiatric disorders, metabolic disorders, metabolic disorders, andreproductive disorders.

Exemplary cardiac disorders include hypertension, dyslipidemia, ischemicheart disease, cardiomyopathy, cardiac infarction, stroke, venousthromboembolic disease and pulmonary hypertension. Exemplary endocrinedisorders include type 2 diabetes and latent autoimmune diabetes inadults. Exemplary respiratory disorders include obesity-hypoventilationsyndrome, asthma, and obstructive sleep apnea. An exemplary hepaticdisorder is nonalcoholic fatty liver disease. Exemplary skeletaldisorders include back pain and osteoarthritis of weight-bearing joints.Exemplary metabolic disorders include Prader-Willi Syndrome andpolycystic ovary syndrome. Exemplary reproductive disorders includesexual dysfunction, erectile dysfunction, infertility, obstetriccomplications, and fetal abnormalities. Exemplary psychiatric disordersinclude weight-associated depression and anxiety.

In particular, in certain embodiments, the disclosure provides a methodof treating the above medical indications comprising administering to asubject in need thereof a therapeutically effective amount of a compounddescribed herein.

Obesity or reference to “overweight” refer to an excess of fat inproportion to lean body mass. Excess fat accumulation is associated withincrease in size (hypertrophy) as well as number (hyperplasia) ofadipose tissue cells. Obesity is variously measured in terms of absoluteweight, weight:height ratio, distribution of subcutaneous fat, andsocietal and esthetic norms. A common measure of body fat is Body MassIndex (BMI). The BMI refers to the ratio of body weight (expressed inkilograms) to the square of height (expressed in meters). Body massindex may be accurately calculated using either of the formulas: weight(kg)/height²(m²) (SI) or 703×weight (lb)/height²(in²) (US).

In accordance with the U.S. Centers for Disease Control and Prevention(CDC), an overweight adult has a BMI of 25 kg/m² to 29.9 kg/m², and anobese adult has a BMI of 30 kg/m² or greater. A BMI of 40 kg/m² orgreater is indicative of morbid obesity or extreme obesity. Obesity canalso refer to patients with a waist circumference of about 102 cm formales and about 88 cm for females. For children, the definitions ofoverweight and obese take into account age and gender effects on bodyfat. Patients with differing genetic background may be consideredconsidered “obese” at a level differing from the general guidelines,above.

The disclosed compounds may also be useful for reducing the risk ofsecondary outcomes of obesity, such as reducing the risk of leftventricular hypertrophy. Methods for treating patients at risk ofobesity, such as those patients who are overweight, but not obese, e.g.with a BMI of between about 25 and 30 kg/m², are also contemplated. Incertain embodiments, a patient is a human.

BMI does not account for the fact that excess adipose can occurselectively in different parts of the body, and development of adiposetissue can be more dangerous to health in some parts of the body ratherthan in other parts of the body. For example, “central obesity”,typically associated with an “apple-shaped” body, results from excessadiposity especially in the abdominal region, including belly fat andvisceral fat, and carries higher risk of co-morbidity than “peripheralobesity”, which is typically associated with a “pear-shaped” bodyresulting from excess adiposity especially on the hips. Measurement ofwaist/hip circumference ratio (WHR) can be used as an indicator ofcentral obesity. A minimum WHR indicative of central obesity has beenvariously set, and a centrally obese adult typically has a WHR of about0.85 or greater if female and about 0.9 or greater if male.

Methods of determining whether a subject is overweight or obese thataccount for the ratio of excess adipose tissue to lean body mass involveobtaining a body composition of the subject. Body composition can beobtained by measuring the thickness of subcutaneous fat in multipleplaces on the body, such as the abdominal area, the subscapular region,arms, buttocks and thighs. These measurements are then used to estimatetotal body fat with a margin of error of approximately four percentagepoints. Another method is bioelectrical impedance analysis (BIA), whichuses the resistance of electrical flow through the body to estimate bodyfat. Another method is using a large tank of water to measure bodybuoyancy. Increased body fat will result in greater buoyancy, whilegreater muscle mass will result in a tendency to sink.

In another aspect, the disclosure provides methods for treating anoverweight or obese subject involving determining a level of at leastone biomarker related to being overweight or obese in the subject, andadministering an effective amount of a disclosed compound to achieve atarget level in the subject. Exemplary biomarkers include body weight,Body Mass Index (BMI), Waist/Hip ratio WHR, plasma adipokines, and acombination of two or more thereof.

In some embodiments, disclosed compounds may not be available to aparticular biotissue, which may result in fewer side effects (e.g.,resulting in minimal or no involvement of other tissues such as thetestes. For example, in some embodiments, compound A, uponadministration, may have significantly less concentration in the testesas compared to concentration in the testes of a male patient of otherMetAP-2 inhibitors (e.g. fumigillin (compound (i), or 201), or ascompared to fumigillol derivatives such

(compound (ii), compound (iii)-fumigillol-compound 203, (iv)

(440); or compound 230:

upon administration.

The compounds of the invention may be administered to patients (animals(e.g. cats, dogs, and/or other companion animals or humans) in need ofsuch treatment in dosages that will provide optimal pharmaceuticalefficacy. It will be appreciated that the dose required for use in anyparticular application will vary from patient to patient, not only withthe particular compound or composition selected, but also with the routeof administration, the nature of the condition being treated, the ageand condition of the patient, concurrent medication or special dietsthen being followed by the patient, and other factors which thoseskilled in the art will recognize, with the appropriate dosageultimately being at the discretion of the attendant physician. Fortreating clinical conditions and diseases noted above, a compound ofthis invention may be administered orally, subcutaneously, topically,parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. Parenteral administrationmay include subcutaneous injections, intravenous or intramuscularinjections or infusion techniques.

Treatment can be continued for as long or as short a period as desired.The compositions may be administered on a regimen of, for example, oneto four or more times per day. A suitable treatment period can be, forexample, at least about one week, at least about two weeks, at leastabout one month, at least about six months, at least about 1 year, orindefinitely. A treatment period can terminate when a desired result,for example a weight loss target, is achieved. A treatment regimen caninclude a corrective phase, during which dose sufficient to providereduction of weight is administered, and can be followed by amaintenance phase, during which a e.g. ower dose sufficient to weightgain is administered. A suitable maintenance dose is likely to be foundin the lower parts of the dose ranges provided herein, but correctiveand maintenance doses can readily be established for individual subjectsby those of skill in the art without undue experimentation, based on thedisclosure herein. Maintenance doses can be employed to maintain bodyweight in subjects whose body weight has been previously controlled byother means, including diet and exercise, bariatric procedures such asbypass or banding surgeries, or treatments employing otherpharmacological agents.

Another aspect of the disclosure provides pharmaceutical compositionscomprising compounds as disclosed herein formulated together with apharmaceutically acceptable carrier. In particular, the presentdisclosure provides pharmaceutical compositions comprising compounds asdisclosed herein formulated together with one or more pharmaceuticallyacceptable carriers. These formulations include those suitable for oral,rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular,intradermal, or intravenous) rectal, vaginal, or aerosol administration,although the most suitable form of administration in any given case willdepend on the degree and severity of the condition being treated and onthe nature of the particular compound being used. For example, disclosedcompositions may be formulated as a unit dose, and/or may be formulatedfor oral or subcutaneous administration.

Exemplary pharmaceutical compositions of this invention may be used inthe form of a pharmaceutical preparation, for example, in solid,semisolid or liquid form, which contains one or more of the compound ofthe invention, as an active ingredient, in admixture with an organic orinorganic carrier or excipient suitable for external, enteral orparenteral applications. The active ingredient may be compounded, forexample, with the usual non-toxic, pharmaceutically acceptable carriersfor tablets, pellets, capsules, suppositories, solutions, emulsions,suspensions, and any other form suitable for use. The active objectcompound is included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or conditionof the disease.

For preparing solid compositions such as tablets, the principal activeingredient may bemixed with a pharmaceutical carrier, e.g., conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g., water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the invention, or a non-toxic pharmaceutically acceptablesalt thereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers, such assodium citrate or dicalcium phosphate, and/or any of the following: (1)fillers or extenders, such as starches, lactose, sucrose, glucose,mannitol, and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, acetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.In the case of capsules, tablets and pills, the compositions may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugars, as well as high molecularweight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the subject compositionmoistened with an inert liquid diluent. Tablets, and other solid dosageforms, such as dragees, capsules, pills and granules, may optionally bescored or prepared with coatings and shells, such as enteric coatingsand other coatings well known in the pharmaceutical-formulating art.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. Liquid dosage forms for oraladministration include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the subject composition, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, solubilizing agents and emulsifiers, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, cyclodextrins and mixtures thereof.

Suspensions, in addition to the subject composition, may containsuspending agents as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing a subject composition withone or more suitable non-irritating excipients or carriers comprising,for example, cocoa butter, polyethylene glycol, a suppository wax or asalicylate, and which is solid at room temperature, but liquid at bodytemperature and, therefore, will melt in the body cavity and release theactive agent.

Dosage forms for transdermal administration of a subject compositionincludes powders, sprays, ointments, pastes, creams, lotions, gels,solutions, patches and inhalants. The active component may be mixedunder sterile conditions with a pharmaceutically acceptable carrier, andwith any preservatives, buffers, or propellants which may be required.

The ointments, pastes, creams and gels may contain, in addition to asubject composition, excipients, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays may contain, in addition to a subject composition,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays may additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Compositions and compounds of the present invention may alternatively beadministered by aerosol. This is accomplished by preparing an aqueousaerosol, liposomal preparation or solid particles containing thecompound. A non-aqueous (e.g., fluorocarbon propellant) suspension couldbe used. Sonic nebulizers may be used because they minimize exposing theagent to shear, which may result in degradation of the compoundscontained in the subject compositions. Ordinarily, an aqueous aerosol ismade by formulating an aqueous solution or suspension of a subjectcomposition together with conventional pharmaceutically acceptablecarriers and stabilizers. The carriers and stabilizers vary with therequirements of the particular subject composition, but typicallyinclude non-ionic surfactants (Tweens, Pluronics, or polyethyleneglycol), innocuous proteins like serum albumin, sorbitan esters, oleicacid, lecithin, amino acids such as glycine, buffers, salts, sugars orsugar alcohols. Aerosols generally are prepared from isotonic solutions.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise a subject composition in combination with one ormore pharmaceutically-acceptable sterile isotonic aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate and cyclodextrins. Proper fluidity may be maintained,for example, by the use of coating materials, such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants

In another aspect, the invention provides enteral pharmaceuticalformulations including a disclosed compound an enteric material; and apharmaceutically acceptable carrier or excipient thereof. Entericmaterials refer to polymers that are substantially insoluble in theacidic environment of the stomach, and that are predominantly soluble inintestinal fluids at specific pHs. The small intestine is the part ofthe gastrointestinal tract (gut) between the stomach and the largeintestine, and includes the duodenum, jejunum, and ileum. The pH of theduodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH ofthe distal ileum is about 7.5. Accordingly, enteric materials are notsoluble, for example, until a pH of about 5.0, of about 5.2, of about5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary entericmaterials include cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP),hydroxypropyl methylcellulose acetate succinate (HPMCAS), celluloseacetate trimellitate, hydroxypropyl methylcellulose succinate, celluloseacetate succinate, cellulose acetate hexahydrophthalate, cellulosepropionate phthalate, cellulose acetate maleat, cellulose acetatebutyrate, cellulose acetate propionate, copolymer of methylmethacrylicacid and methyl methacrylate, copolymer of methyl acrylate,methylmethacrylate and methacrylic acid, copolymer of methylvinyl etherand maleic anhydride (Gantrez ES series), ethylmethyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylatecopolymer, natural resins such as zein, shellac and copal collophorium,and several commercially available enteric dispersion systems (e. g.,Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, KollicoatEMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of eachof the above materials is either known or is readily determinable invitro. The foregoing is a list of possible materials, but one of skillin the art with the benefit of the disclosure would recognize that it isnot comprehensive and that there are other enteric materials that wouldmeet the objectives of the present invention.

Advantageously, the invention also provides kits for use by a e.g. aconsumer in need of weight loss. Such kits include a suitable dosageform such as those described above and instructions describing themethod of using such dosage form to mediate, reduce or preventinflammation. The instructions would direct the consumer or medicalpersonnel to administer the dosage form according to administrationmodes known to those skilled in the art. Such kits could advantageouslybe packaged and sold in single or multiple kit units. An example of sucha kit is a so-called blister pack. Blister packs are well known in thepackaging industry and are being widely used for the packaging ofpharmaceutical unit dosage forms (tablets, capsules, and the like).Blister packs generally consist of a sheet of relatively stiff materialcovered with a foil of a preferably transparent plastic material. Duringthe packaging process recesses are formed in the plastic foil. Therecesses have the size and shape of the tablets or capsules to bepacked. Next, the tablets or capsules are placed in the recesses and thesheet of relatively stiff material is sealed against the plastic foil atthe face of the foil which is opposite from the direction in which therecesses were formed. As a result, the tablets or capsules are sealed inthe recesses between the plastic foil and the sheet. Preferably thestrength of the sheet is such that the tablets or capsules can beremoved from the blister pack by manually applying pressure on therecesses whereby an opening is formed in the sheet at the place of therecess. The tablet or capsule can then be removed via said opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of a first compound can consistof one tablet or capsule while a daily dose of the second compound canconsist of several tablets or capsules and vice versa. The memory aidshould reflect this.

Also contemplated herein are methods and compositions that include asecond active agent, or administering a second active agent. Forexample, in addition to being overweight or obese, a subject or patientcan further have overweight- or obesity-related co-morbidities, i.e.,diseases and other adverse health conditions associated with,exacerbated by, or precipitated by being overweight or obese.Contemplated herein are disclosed compounds in combination with at leastone other agent that has previously been shown to treat theseoverweight- or obesity-related conditions.

For example, Type II diabetes has been associated with obesity. Certaincomplications of Type II diabetes, e.g., disability and premature death,can be prevented, ameliorated, or eliminated by sustained weight loss(Astrup, A. Pub Health Nutr (2001) 4:499-5 15). Agents administered totreat Type II diabetes include sulfonylureas (e.g., Chlorpropamide,Glipizide, Glyburide, Glimepiride); meglitinides (e.g., Repaglinide andNateglinide); biguanides (e.g., Metformin); thiazolidinediones(Rosiglitazone, Troglitazone, and Pioglitazone); dipeptidylpeptidase-4inhibitors (e.g., Sitagliptin, Vildagliptin, and Saxagliptin);glucagon-like peptide-1 mimetics (e.g., Exenatide and Liraglutide); andalpha-glucosidase inhibitors (e.g., Acarbose and Miglitol.

Cardiac disorders and conditions, for example hypertension,dyslipidemia, ischemic heart disease, cardiomyopathy, cardiacinfarction, stroke, venous thromboembolic disease and pulmonaryhypertension, have been linked to overweight or obesity. For example,hypertension has been linked to obesity because excess adipose tissuesecretes substances that are acted on by the kidneys, resulting inhypertension. Additionally, with obesity there are generally higheramounts of insulin produced (because of the excess adipose tissue) andthis excess insulin also elevates blood pressure. A major treatmentoption of hypertension is weight loss. Agents administered to treathypertension include Chlorthalidone; Hydrochlorothiazide; Indapamide,Metolazone; loop diuretics (e.g., Bumetanide, Ethacrynic acid,Furosemide, Lasix, Torsemide); potassium-sparing agents (e g, Amiloridehydrochloride, benzamil, Spironolactone, and Triamterene); peripheralagents (e.g., Reserpine); central alpha-agonists (e.g., Clonidinehydrochloride, Guanabenz acetate, Guanfacine hydrochloride, andMethyldopa); alpha-blockers (e.g., Doxazosin mesylate, Prazosinhydrochloride, and Terazosin hydrochloride); beta-blockers (e.g.,Acebutolol, Atenolol, Betaxolol, Bisoprolol fumarate, Carteololhydrochloride, Metoprolol tartrate, Metoprolol succinate, Nadolol,Penbutolol sulfate, Pindolol, Propranolol hydrochloride, and Timololmaleate); combined alpha- and beta-blockers (e.g., Carvedilol andLabetalol hydrochloride); direct vasodilators (e.g., Hydralazinehydrochloride and Minoxidil); calcium antagonists (e.g., Diltiazemhydrochloride and Verapamil hydrochloride); dihydropyridines (e.g.,Amlodipine besylate, Felodipine, Isradipine, Nicardipine, Nifedipine,and Nisoldipine); ACE inhibitors (benazepril hydrochloride, Captopril,Enalapril maleate, Fosinopril sodium, Lisinopril, Moexipril, Quinaprilhydrochloride, Ramipril, Trandolapril); Angiotensin II receptor blockers(e.g., Losartan potassium, Valsartan, and Irbesartan); Renin inhibitors(e.g., Aliskiren); and combinations thereof. These compounds areadministered in regimens and at dosages known in the art.

Carr et al. (The Journal of Clinical Endocrinology & Metabolism (2004)Vol. 89, No. 6 2601-2607) discusses a link between being overweight orobese and dyslipidemia. Dyslipidemia is typically treated with statins.Statins, HMG-CoA reductase inhibitors, slow down production ofcholesterol in a subject and/or remove cholesterol buildup fromarteries. Statins include mevastatin, lovastatin, pravastatin,simvastatin, velostatin, dihydrocompactin, fluvastatin, atorvastatin,dalvastatin, carvastatin, crilvastatin, bevastatin, cefvastatin,rosuvastatin, pitavastatin, and glenvastatin. These compounds areadministered in regimens and at dosages known in the art. Eckel(Circulation (1997) 96:3248-3250) discusses a link between beingoverweight or obese and ischemic heart disease. Agents administered totreat ischemic heart disease include statins, nitrates (e.g., IsosorbideDinitrate and Isosorbide Mononitrate), beta-blockers, and calciumchannel antagonists. These compounds are administered in regimens and atdosages known in the art.

Wong et al. (Nature Clinical Practice Cardiovascular Medicine (2007)4:436-443) discusses a link between being overweight or obese andcardiomyopathy. Agents administered to treat cardiomyopathy includeinotropic agents (e.g., Digoxin), diuretics (e.g., Furosemide), ACEinhibitors, calcium antagonists, anti-arrhythmic agents (e.g., Sotolol,Amiodarone and Disopyramide), and beta-blockers. These compounds areadministered in regimens and at dosages known in the art. Yusef et al.(Lancet (2005) 366(9497):1640-1649) discusses a link between beingoverweight or obese and cardiac infarction. Agents administered to treatcardiac infarction include ACE inhibitors, Angiotensin II receptorblockers, direct vasodilators, beta blockers, anti-arrhythmic agents andthrombolytic agents (e.g., Alteplase, Retaplase, Tenecteplase,Anistreplase, and Urokinase). These compounds are administered inregimens and at dosages known in the art.

Suk et al. (Stroke (2003) 34:1586-1592) discusses a link between beingoverweight or obese and strokes. Agents administered to treat strokesinclude anti-platelet agents (e.g., Aspirin, Clopidogrel, Dipyridamole,and Ticlopidine), anticoagulant agents (e.g., Heparin), and thrombolyticagents. Stein et al. (The American Journal of Medicine (2005)18(9):978-980) discusses a link between being overweight or obese andvenous thromboembolic disease. Agents administered to treat venousthromboembolic disease include anti-platelet agents, anticoagulantagents, and thrombolytic agents. Sztrymf et al. (Rev Pneumol Clin (2002)58(2):104-10) discusses a link between being overweight or obese andpulmonary hypertension. Agents administered to treat pulmonaryhypertension include inotropic agents, anticoagulant agents, diuretics,potassium (e.g., K-dur), vasodilators (e.g., Nifedipine and Diltiazem),Bosentan, Epoprostenol, and Sildenafil. Respiratory disorders andconditions such as obesity-hypoventilation syndrome, asthma, andobstructive sleep apnea, have been linked to being overweight or obese.Elamin (Chest (2004) 125:1972-1974) discusses a link between beingoverweight or obese and asthma. Agents administered to treat asthmainclude bronchodilators, anti-inflammatory agents, leukotriene blockers,and anti-Ige agents. Particular asthma agents include Zafirlukast,Flunisolide, Triamcinolone, Beclomethasone, Terbutaline, Fluticasone,Formoterol, Beclomethasone, Salmeterol, Theophylline, and Xopenex.

Kessler et al. (Eur Respir J (1996) 9:787-794) discusses a link betweenbeing overweight or obese and obstructive sleep apnea. Agentsadministered to treat sleep apnea include Modafinil and amphetamines.

Hepatic disorders and conditions, such as nonalcoholic fatty liverdisease, have been linked to being overweight or obese. Tolman et al.(Ther Clin Risk Manag (2007) 6:1153-1163) discusses a link between beingoverweight or obese and nonalcoholic fatty liver disease. Agentsadministered to treat nonalcoholic fatty liver disease includeantioxidants (e.g., Vitamins E and C), insulin sensitizers (Metformin,Pioglitazone, Rosiglitazone, and Betaine), hepatoprotectants, andlipid-lowering agents.

Skeletal disorders and conditions, such as, back pain and osteoarthritisof weight-bearing joints, have been linked to being overweight or obese.van Saase (J Rheumatol (1988) 15(7):1152-1158) discusses a link betweenbeing overweight or obese and osteoarthritis of weight-bearing joints.Agents administered to treat osteoarthritis of weight-bearing jointsinclude Acetaminophen, non-steroidal anti-inflammatory agents (e.g.,Ibuprofen, Etodolac, Oxaprozin, Naproxen, Diclofenac, and Nabumetone),COX-2 inhibitors (e.g., Celecoxib), steroids, supplements (e.g.glucosamine and chondroitin sulfate), and artificial joint fluid.

Metabolic disorders and conditions, for example, Prader-Willi Syndromeand polycystic ovary syndrome, have been linked to being overweight orobese. Cassidy (Journal of Medical Genetics (1997) 34:917-923) discussesa link between being overweight or obese and Prader-Willi Syndrome.Agents administered to treat Prader-Willi Syndrome include human growthhormone (HGH), somatropin, and weight loss agents (e.g., Orlistat,Sibutramine, Methamphetamine, Ionamin, Phentermine, Bupropion,Diethylpropion, Phendimetrazine, Benzphetermine, and Topamax).

Hoeger (Obstetrics and Gynecology Clinics of North America (2001)28(1):85-97) discusses a link between being overweight or obese andpolycystic ovary syndrome. Agents administered to treat polycystic ovarysyndrome include insulin-sensitizers, combinations of synthetic estrogenand progesterone, Spironolactone, Eflornithine, and Clomiphene.Reproductive disorders and conditions such as sexual dysfunction,erectile dysfunction, infertility, obstetric complications, and fetalabnormalities, have been linked to being overweight or obese. Larsen etal. (Int J Obes (Lond) (2007) 8:1189-1198) discusses a link betweenbeing overweight or obese and sexual dysfunction. Chung et al. (Eur Urol(1999) 36(1):68-70) discusses a link between being overweight or obeseand erectile dysfunction. Agents administered to treat erectiledysfunction include phosphodiesterase inhibitors (e.g., Tadalafil,Sildenafil citrate, and Vardenafil), prostaglandin E analogs (e.g.,Alprostadil), alkaloids (e.g., Yohimbine), and testosterone. Pasquali etal. (Hum Reprod (1997) 1:82-87) discusses a link between beingoverweight or obese and infertility. Agents administered to treatinfertility include Clomiphene, Clomiphene citrate, Bromocriptine,Gonadotropin-releasing Hormone (GnRH), GnRH agonist, GnRH antagonist,Tamoxifen/nolvadex, gonadotropins, Human Chorionic Gonadotropin (HCG),Human Menopausal Gonadotropin (HmG), progesterone, recombinant folliclestimulating hormone (FSH), Urofollitropin, Heparin, Follitropin alfa,and Follitropin beta.

Weiss et al. (American Journal of Obstetrics and Gynecology (2004)190(4):1091-1097) discusses a link between being overweight or obese andobstetric complications. Agents administered to treat obstetriccomplications include Bupivacaine hydrochloride, Dinoprostone PGE2,Meperidine HCl, Ferro-folic-500/iberet-folic-500, Meperidine,Methylergonovine maleate, Ropivacaine HCl, Nalbuphine HCl, OxymorphoneHCl, Oxytocin, Dinoprostone, Ritodrine, Scopolamine hydrobromide,Sufentanil citrate, and Oxytocic.

Psychiatric disorders and conditions, for example, weight-associateddepression and anxiety, have been linked to being overweight or obese.Dixson et al. (Arch Intern Med (2003) 163:2058-2065) discusses a linkbetween being overweight or obese and depression. Agents administered totreat depression include serotonin reuptake inhibitors (e.g.,Fluoxetine, Escitalopram, Citalopram, Paroxetine, Sertraline, andVenlafaxine); tricyclic antidepressants (e.g., Amitriptyline, Amoxapine,Clomipramine, Desipramine, Dosulepin hydrochloride, Doxepin, Imipramine,Iprindole, Lofepramine, Nortriptyline, Opipramol, Protriptyline, andTrimipramine); monoamine oxidase inhibitors (e.g., Isocarboxazid,Moclobemide, Phenelzine, Tranylcypromine, Selegiline, Rasagiline,Nialamide, Iproniazid, Iproclozide, Toloxatone, Linezolid, Dienolidekavapyrone desmethoxyyangonin, and Dextroamphetamine); psychostimulants(e.g., Amphetamine, Methamphetamine, Methylphenidate, and Arecoline);antipsychotics (e.g., Butyrophenones, Phenothiazines, Thioxanthenes,Clozapine, Olanzapine, Risperidone, Quetiapine, Ziprasidone,Amisulpride, Paliperidone, Symbyax, Tetrabenazine, and Cannabidiol); andmood stabilizers (e.g., Lithium carbonate, Valproic acid, Divalproexsodium, Sodium valproate, Lamotrigine, Carbamazepine, Gabapentin,Oxcarbazepine, and Topiramate).

Simon et al. (Archives of General Psychiatry (2006) 63(7):824-830)discusses a link between being overweight or obese and anxiety. Agentsadministered to treat anxiety include serotonin reuptake inhibitors,mood stabilizers, benzodiazepines (e.g., Alprazolam, Clonazepam,Diazepam, and Lorazepam), tricyclic antidepressants, monoamine oxidaseinhibitors, and beta-blockers.

Another aspect of the invention provides methods for facilitating andmaintaining weight loss in a subject involving administering to thesubject an amount of a disclosed compound effective to result in weightloss in the subject; and administering a therapeutically effectiveamount of a different weight loss agent to maintain a reduced weight inthe subject. Weight loss agents include serotonin and noradrenergicre-uptake inhibitors; noradrenergic re-uptake inhibitors; selectiveserotonin re-uptake inhibitors; and intestinal lipase inhibitors.Particular weight loss agents include orlistat, sibutramine,methamphetamine, ionamin, phentermine, bupropion, diethylpropion,phendimetrazine, benzphetermine, bromocriptine, lorcaserin, topiramate,or agents acting to modulate food intake by blocking ghrelin action,inhibiting diacylglycerol acyltransferase 1 (DGAT1) activity, inhibitingstearoyl CoA desaturase 1 (SCD1) activity, inhibiting neuropeptide Yreceptor 1 function, activating neuropeptide Y receptor 2 or 4 function,or inhibiting activity of sodium-glucose cotransporters 1 or 2. Thesecompounds are administered in regimens and at dosages known in the art.

EXAMPLES

Compounds may be identified by number, which may be referred to in someinstances with a prefix ZGN.

Example 1 Compound 444

In a round bottom flask under nitrogen 100 mg (0.23 mmol) ofintermediate A was dissolved in 4 mL of CH₂Cl₂ and 0.12 g of DIPEA (0.92mmol) was added followed by 63 mg (0.7 mmol) of 1,1-dimethyl-2-aminoethanol. The mixture was allowed to stir overnight and then condensed invacuo. The residue was dissolved in 20 mL of EtOAc and washed with 2×20mL of water, 20 mL of brine, dried over Na₂SO₄ and condensed in vacuo.Purification by biotage flash chromatography (SiO2, MeOH/CH₂Cl₂/Et₃Ngradient) affords 38 mg of the title compound as a clear viscous oil.

Example 2—Compound 445

In a round bottom flask under nitrogen 150 mg (0.35 mmol) ofintermediate A was dissolved in 5 mL of CH₂Cl₂ and 0.18 g of DIPEA (1.4mmol) was added followed by 91 mg (1.05 mmol) of 3-hydroxy pyrrolidine.The mixture was allowed to stir overnight and then condensed in vacuo.The residue was dissolved in 20 mL of EtOAc and washed with 2×20 mL ofwater, 20 mL of brine, dried over Na₂SO₄ and condensed in vacuo.Purification by biotage flash chromatography (SiO2, MeOH/CH₂Cl₂/Et₃Ngradient) affords 41 mg of the title compound as a clear viscous oil.

Example 3—Compound 446

In a round bottom flask under nitrogen 100 mg (0.23 mmol) ofintermediate A was dissolved in 4 mL of CH₂Cl₂ and 0.12 g of DIPEA (0.92mmol) was added followed by 50 mg (0.7 mmol) of2-(hydroxymethyl)-pyrrolidine. The mixture was allowed to stir overnightand then condensed in vacuo. The residue was dissolved in 20 mL of EtOAcand washed with 2×20 mL of water, 20 mL of brine, dried over Na₂SO₄ andcondensed in vacuo. Purification by biotage flash chromatography (SiO2,MeOH/CH₂Cl₂/Et₃N gradient) affords 58 mg of the title compound.

Example 4-Compound 447

In a round bottom flask under nitrogen 150 mg (0.35 mmol) ofintermediate A was dissolved in 5 mL of CH₂Cl₂ and 0.18 g of DIPEA (1.4mmol) was added followed by 136 mg (1.05 mmol) of 3-hydroxy pyrrolidine.The mixture was allowed to stir overnight and then condensed in vacuo.The residue was dissolved in 20 mL of EtOAc and washed with 2×20 mL ofwater, 20 mL of brine, dried over Na₂SO₄ and condensed in vacuo.Purification by biotage flash chromatography (SiO2, MeOH/CH₂Cl₂/Et₃Ngradient) affords 93 mg of the title compound as a white solid.

Example 5-Compound 448

In a round bottom flask under nitrogen 100 mg (0.23 mmol) ofintermediate A was dissolved in 4 mL of CH₂Cl₂ and 0.12 g of DIPEA (0.92mmol) was added followed by 42 ul (0.7 mmol) of 2-hydroxy-ethylamine.The mixture was allowed to stir overnight and then condensed in vacuo.The residue was dissolved in 20 mL of EtOAc and washed with 2×20 mL ofwater, 20 mL of brine, dried over Na₂SO₄ and condensed in vacuo.Purification by biotage flash chromatography (SiO2, MeOH/CH₂Cl₂/Et₃Ngradient) affords 32 mg of the title compound as a clear oil.

Example 6—Compound 449

In a round bottom flask under nitrogen 100 mg (0.23 mmol) ofintermediate A was dissolved in 4 mL of CH₂Cl₂ and 0.12 g of DIPEA (0.92mmol) was added followed by 53 ul (0.7 mmol) of 2-methoxy-ethylamine.The mixture was allowed to stir overnight and then condensed in vacuo.The residue was dissolved in 20 mL of EtOAc and washed with 2×20 mL ofwater, 20 mL of brine, dried over Na₂SO₄ and condensed in vacuo.Purification by biotage flash chromatography (SiO2, MeOH/CH₂Cl₂/Et₃Ngradient) affords 51 mg of the title compound as a clear oil.

Example 7-Compound 450

In a round bottom flask under nitrogen 150 mg (0.35 mmol) ofintermediate A was dissolved in 5 mL of CH₂Cl₂ and 0.18 g of DIPEA (1.4mmol) was added followed by 125 mg (1.05 mmol) of2-(2-Methoxy-ethoxy)-ethylamine. The mixture was allowed to stirovernight and then condensed in vacuo. The residue was dissolved in 20mL of EtOAc and washed with 2×20 mL of water, 20 mL of brine, dried overNa₂SO₄ and condensed in vacuo. Purification by biotage flashchromatography (SiO₂, MeOH/CH₂Cl₂/Et₃N gradient) affords 99 mg of thetitle compound as a clear oil

Example 8—Compound 451

In a round bottom flask under nitrogen 150 mg (0.35 mmol) ofintermediate A was dissolved in 5 mL of CH₂Cl₂ and 0.18 g of DIPEA (1.4mmol) was added followed by 150 mg (1.05 mmol) of 2-amino-3-methylbutanoic acid dimethylamide. The mixture was allowed to stir overnightand then condensed in vacuo. The residue was dissolved in 20 mL of EtOAcand washed with 2×20 mL of water, 20 mL of brine, dried over Na₂SO₄ andcondensed in vacuo. Purification by biotage flash chromatography (SiO2,MeOH/CH₂Cl₂/Et₃N gradient) affords 81 mg of the title compound as aclear oil.

Example 9—Compound 452

In a round bottom flask under nitrogen 150 mg (0.35 mmol) ofintermediate A was dissolved in 5 mL of CH₂Cl₂ and 0.18 g of DIPEA (1.4mmol) was added followed by 0.5 ml (1.05 mmol) of dimethyl amine. Themixture was allowed to stir overnight and then condensed in vacuo. Theresidue was dissolved in 20 mL of EtOAc and washed with 2×20 mL ofwater, 20 mL of brine, dried over Na₂SO₄ and condensed in vacuo.Purification by biotage flash chromatography (SiO2, MeOH/CH₂Cl₂/Et₃Ngradient) affords 51 mg of the title compound.

Example 10-Compound 453

In a round bottom flask under nitrogen 100 mg (0.23 mmol) ofintermediate A was dissolved in 4 mL of CH₂Cl₂ and 0.12 g of DIPEA (0.92mmol) was added followed by 50 mg (0.7 mmol) of pyrrolidine. The mixturewas allowed to stir overnight and then condensed in vacuo. The residuewas dissolved in 20 mL of EtOAc and washed with 2×20 mL of water, 20 mLof brine, dried over Na₂SO₄ and condensed in vacuo. Purification bybiotage flash chromatography (SiO2, MeOH/CH₂Cl₂/Et₃N gradient) affords62 mg of the title compound as a clear viscous oil.

Example 11-Compound 454

In a round bottom flask under nitrogen 150 mg (0.35 mmol) ofintermediate A was dissolved in 5 mL of CH₂Cl₂ and 0.18 g of DIPEA (1.4mmol) was added followed by 91 mg (1.05 mmol) of 3-hydroxy-3-methylazetidine. The mixture was allowed to stir overnight and then condensedin vacuo. The residue was dissolved in 20 mL of EtOAc and washed with2×20 mL of water, 20 mL of brine, dried over Na₂SO₄ and condensed invacuo. Purification by biotage flash chromatography (SiO2,MeOH/CH₂Cl₂/Et₃N gradient) affords 82 mg of the title compound as aclear viscous oil.

Example 12-Compound 455

In a round bottom flask under nitrogen 150 mg (0.35 mmol) ofintermediate A was dissolved in 5 mL of CH₂Cl₂ and 0.18 g of DIPEA (1.4mmol) was added followed by 108 mg (1.05 mmol) of pyrrolidine-3,4-diol.The mixture was allowed to stir overnight and then condensed in vacuo.The residue was dissolved in 20 mL of EtOAc and washed with 2×20 mL ofwater, 20 mL of brine, dried over Na₂SO₄ and condensed in vacuo.Purification by biotage flash chromatography (SiO2, MeOH/CH₂Cl₂/Et₃Ngradient) affords 43 mg of the title compound as a clear viscous oil.

Example 13-Compound 456

In a round bottom flask under nitrogen 150 mg (0.35 mmol) ofintermediate A was dissolved in 5 mL of CH₂Cl₂ and 0.18 g of DIPEA (1.4mmol) was added followed by 110 mg (1.05 mmol) of 3-hydroxy azetidine.The mixture was allowed to stir overnight and then condensed in vacuo.The residue was dissolved in 20 mL of EtOAc and washed with 2×20 mL ofwater, 20 mL of brine, dried over Na₂SO₄ and condensed in vacuo.Purification by biotage flash chromatography (SiO2, MeOH/CH₂Cl₂/Et₃Ngradient) affords 43 mg of the title compound as a clear viscous oil.

Example 14-compound 457

In a round bottom flask under nitrogen 100 mg (0.23 mmol) ofintermediate A was dissolved in 4 mL of CH₂Cl₂ and 0.12 g of DIPEA (0.92mmol) was added followed by 108 mg (0.7 mmol) of2-Methoxy-2-methyl-propylamine. The mixture was allowed to stirovernight and then condensed in vacuo. The residue was dissolved in 20mL of EtOAc and washed with 2×20 mL of water, 20 mL of brine, dried overNa₂SO₄ and condensed in vacuo. Purification by biotage flashchromatography (SiO2, MeOH/CH₂Cl₂/Et₃N gradient) affords 71 mg of thetitle compound as a clear viscous oil.

Example 15-Compound 258

In a round bottom flask under nitrogen 150 mg (0.35 mmol) ofintermediate A was dissolved in 5 mL of CH₂Cl₂ and 0.18 g of DIPEA (1.4mmol) was added followed by 170 mg (1.05 mmol) of 2-amino-3-methylbutanoic acid methylamide. The mixture was allowed to stir overnight andthen condensed in vacuo. The residue was dissolved in 20 mL of EtOAc andwashed with 2×20 mL of water, 20 mL of brine, dried over Na₂SO₄ andcondensed in vacuo. Purification by biotage flash chromatography (SiO2,MeOH/CH₂Cl₂/Et₃N gradient) affords 33 mg of the title compound as aclear oil.

Example 16-Compound 256

1 g (3.5 mmol) of the fumagillol is dissolved in 15 ml of ethanol and380 mg (0.35 mmol) of Pd/C is added. The flask is capped and evacuatedand back filled with nitrogen three times. Then the flask is evacuatedand backfilled with hydrogen. The mixture is stirred at room temperaturefor 1 h. After the reaction is complete the flask is evacuated andbackfilled with nitrogen three tomes and then the Pd/C is removed byfiltration through Celite. The solvents are removed in vacuo to give 800mg (81%) of the desired product

Example 17-Compound 459

In a round bottom flask under nitrogen 280 mg (1 mmol) of fumagillol,270 mg (1.16 mmol) of the cinnamic acid derivative, 13.4 mg (0.11 mmol)of DMAP, and 0.22 mL (1.3 mmol) of dissopropyl ethyl amine is dissolvedin 10 ml of hexanes. To the stirred solution is added 0.22 ml (1.16mmol) of pivaloyl anhydride. The reaction is allowed to stir at roomtemp for 6 h at which point an additional 0.22 ml (1.16 mmol) ofpivaloyl anhydride is added. The reaction is allowed to stir over nightand the next day the reaction is diluted with ethyl acetate (50 ml) andwashed with saturated sodium bicarbonate (20 ml) and dried over sodiumsulfate. Purification by flash chromatography (biotage, SiO₂,Methanol/dichloromethane gradient) gives 278 mg of the title compound(55% yield).

200 mg (0.85 mmol) of the unsaturated cinnamic acid derivative isdissolved in 5 ml of ethyl acetate and 9 mg (0.085 mmol) of Pd/C isadded. The flask is capped and evacuated and back filled with nitrogenthree times. Then the flask is evacuated and backfilled with hydrogen.The mixture is stirred at room temperature for 18 h. After the reactionis complete the flask is evacuated and backfilled with nitrogen threetomes and then the Pd/C is removed by filtration through Celite. Thesolvents are removed in vacuo to give 165 mg (81%) of the desiredproduct

Example 17-Compound 460

In a round bottom flask under nitrogen 286 mg (1 mmol) of Compound 256(ZGN-256), 270 mg (1.16 mmol) of the cinnamic acid derivative, 13.4 mg(0.11 mmol) of DMAP, and 0.22 mL (1.3 mmol) of dissopropyl ethyl amineis dissolved in 10 ml of hexanes. To the stirred solution is added 0.22ml (1.16 mmol) of pivaloyl anhydride. The reaction is allowed to stir atroom temp for 6 h at which point an additional 0.22 ml (1.16 mmol) ofpivaloyl anhydride is added. The reaction is allowed to stir over nightand the next day the reaction is diluted with ethyl acetate (50 ml) andwashed with saturated sodium bicarbonate (20 ml) and dried over sodiumsulfate. Purification by flash chromatography (biotage, SiO₂,Methanol/dichloromethane gradient) gives 293 mg of the title compound(58% yield).

Example 18-Compound 461

In a round bottom flask under nitrogen 200 mg (0.7 mmol) of compound256, 160 mg (0.7 mmol) of the cinnamic acid derivative, 9.3 mg (0.07mmol) of DMAP, and 0.16 mL (0.91 mmol) of dissopropyl ethyl amine isdissolved in 10 ml of heptane. To the stirred solution is added 0.14 ml(0.7 mmol) of pivaloyl anhydride. The reaction is allowed to stir overnight and the next day the reaction is diluted with ethyl acetate (50ml) and washed with saturated sodium bicarbonate (20 ml) and dried oversodium sulfate. Purification by flash chromatography (biotage, SiO₂,Methanol/dichloromethane gradient) gives 90 mg of the title compound(24% yield).

Example 19

Studies were conducted using 18-20 week old Diet Induced Obese (DIO)C57BL/6 mice. The study was a 7 day screen that included 18-20 week oldC57BL/6 mice that were provided a high fat diet for 14 weeks, andtreated with compounds injected subcutaneously daily at 0.3 mg/kg. FIG.1 shows the weight loss of effect of this dose for various disclosedcompounds.

Example 20

10 day studies were conducted that included 20 week old C57BL/6 mice onhigh fat diet for 14 weeks treated with either 10% DMSO or the samevehicle containing an amount of drug to deliver a dose of 3 mg/kg PO(oral gavage) of disclosed compounds for 10 days. ZGN-201 control wasdosed at 1 mg/kg PO. ZGN-444 was dosed at both 3 mg/kg and 0.3 mg/kg.FIG. 2A, B, C depicts the 10-day PO efficacy at 3 mg/kg of disclosedcompound. FIG. 2C shows 10-day PO efficicacy at 3 mg/kg for compound 444and other disclosed compounds, indicating the oral efficacy of compound444.

At the end of these studies testes from the mice were harvested,homogenized and digested with endoproteinase Glu-C. The N-terminalpeptide of mouse thioredoxin (a selective substrate of the target enzymeMetAP2 was analyzed by LC-MS/MS for full length peptide amino acid 1-6(SEQ ID NO. 1: MVKLIE), and the degree of detection in a given tissue isindicative of MetAP2 inhibition in that tissue. (See J Proteome Res.2008; 7:4807). FIGS. 3A, B, and C, show the concentration of SEQ ID NO.1 (ng/mL) and indicates that certain compounds are not available to thetestes tissue as compared to the other tested compounds (and thereforemay have fewer testes related side effects). FIG. 3C indicates compound444 administered orally is not available to the testes tissue.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein, including those itemslisted below, are hereby incorporated by reference in their entirety forall purposes as if each individual publication or patent wasspecifically and individually incorporated by reference. In case ofconflict, the present application, including any definitions herein,will control.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification. The full scope of the inventionshould be determined by reference to the claims, along with their fullscope of equivalents, and the specification, along with such variations.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in this specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained by the present invention.

1.-2. (canceled)
 3. A method of treating and/or controlling obesity,comprising administering to a patient in need thereof an effectiveamount of a compound represented by:

wherein R² is selected from the group consisting of hydroxyl andisopropyl (optionally substituted with a hydroxyl); R³ is selected fromthe group consisting of H and hydroxyl; or pharmaceutically acceptablesalts or stereoisomers thereof.
 4. (canceled)
 5. A method of treatingand/or controlling obesity, comprising administering to a patient inneed thereof an effective amount of a compound represented by:

wherein R⁴ and R⁵, together with the nitrogen to which they areattached, form a 4 membered ring optionally substituted by one or twosubstituents independently selected from the group consisting of methyland hydroxyl; or pharmaceutically acceptable salts or stereoisomersthereof.
 6. The method of claim 5, wherein the compound is representedby:

wherein R⁶ is selected from the group consisting of H, hydroxyl andmethyl; and R⁷ is selected from the group consisting of H, hydroxyl andmethyl.
 7. A method of treating and/or controlling obesity, comprisingadministering to a patient in need thereof an effective amount of acompound represented by:

wherein n is 1 or 2; or pharmaceutically acceptable salts orstereoisomers thereof.
 8. A method of treating and/or controllingobesity, comprising administering to a patient in need thereof aneffective amount of a compound selected from the group consisting of:

and pharmaceutically acceptable salts or stereoisomers thereof.
 9. Amethod of treating and/or controlling obesity, comprising administeringto a patient in need thereof an effective amount of a compound selectedfrom the group consisting of:

and pharmaceutically acceptable salts or stereoisomers thereof. 10.-11.(canceled)
 12. The method of claim 3, wherein the patient is a human.13. (canceled)
 14. The method of claim 3, wherein the compound isadministered orally, intravenously, or subcutaneously.
 15. The method ofclaim 3, wherein the compound is administered orally. 16.-18. (canceled)19. The method of claim 5, wherein the patient is a human.
 20. Themethod claim 5, wherein the compound is administered orally,intravenously, or subcutaneously.
 21. The method of claim 5, wherein thecompound is administered orally.
 22. The method of claim 7, wherein thepatient is a human.
 23. The method claim 7, wherein the compound isadministered orally, intravenously, or subcutaneously.
 24. The method ofclaim 7, wherein the compound is administered orally.
 25. The method ofclaim 8, wherein the patient is a human.
 26. The method claim 8, whereinthe compound is administered orally, intravenously, or subcutaneously.27. The method of claim 8, wherein the compound is administered orally.28. The method of claim 9, wherein the patient is a human.
 29. Themethod claim 9, wherein the compound is administered orally,intravenously, or subcutaneously.
 30. The method of claim 9, wherein thecompound is administered orally.